The pharmacophore and stereochemistry

Question 1

how does drug action occur

Answer 1

for a drug molecule to exert a pharmacological effect, an interaction between the drug molecule and the target molecule must occur

Question 2

when can bonding occur

Answer 2

can only occur if the key functional groups are structurally orientated so that they align appropriately with complementary functional groups on target molecule

Question 3

what is a pharmacophore

Answer 3

ensemble of steric and electronic fearers that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger or block its biological response

Question 4

what are pharmacophoric descriptors

Answer 4

used to define a pharmacore, including ionic, H bonding, hydrophobic and electrostatic interaction sites, defined by atoms, ring centres and virtual points

Question 5

what are stereoisomers

Answer 5

isomers that possess identical constitution but which differ in the arrangement of their atoms in space

Question 6

what is stereochemistry

Answer 6

branch of chemistry that deals with spatial arrangements of atoms in molecules and the effects of these arrangements on the chemical and physical properties of substances

Question 7

what is chirality

Answer 7

a molecule is chiral if it is not superimposable on its mirror image regardless of how it is contorted

Question 8

what are enantiomers

Answer 8

molecules that are mirror images of each other but aren’t identical
- rotate the plane of polarised light equally but in opposite directions
- also called optical isomers
- non superimposable mirror images
- have the same physicochemical properties in an achiral environment apart from optical rotation

Question 9

what are diastereoisomers

Answer 9

all stereoisomers that are not enantiomers
- non superimposable non mirror images
- have different physicochemical properties

Question 10

what do most drugs act on

Answer 10

a protein target

Question 11

what are proteins composed of

Answer 11

amino acids

Question 12

describe the structure of proteins

Answer 12

• have primary, secondary, tertiary and quaternary structure
• have a 3 dimensional structure which is determined by a combination of factors

Question 13

what is the protein 3D structure determined by

Answer 13

1. amino acid sequence and interactions between these amino acids
2. interaction with other molecules in immediate environment

Question 14

what is complementarity

Answer 14

the correspondence or similarity between nucleotides or strands of nucleotides of DNA and RNA molecules that allows precise pairing
- the affinity that an antigen and antibody have for each other as a result of the chemical arrangement of their combining sites

Question 15

what is a binding site

Answer 15

a specific region in a molecular entity that is capable of entering into a stabilising interaction with another molecular entity
- eg. active site in an enzyme with its substrate
- typical forms of interaction are by hydrogen bonding, coordination and ion pair formation

Question 16

what is the easson stedman hypothesis

Answer 16

if 2 enantiomers demonstrate different activities at the same target, then 3 sites on a molecule must be involved in the interaction between drug and target
- a 3 point interaction ensure stereoselectivity

Question 17

what is a eutomer

Answer 17

the enantiomer of a chiral compound that is the more potent for a particular action

Question 18

what is the consequence of single enantiomer medicines

Answer 18

any situation in which a chiral drug interacts with another chiral molecule could potentially have stereoselective consequences

Question 19

what are the pharmacodynamic considerations in the interaction between drug molecule and target molecule

Answer 19

1. no difference in activity
   - eg. antiarrhythmic activity of propranolol is not stereoselective
2. quantitative differences
   - distemper may have reduced activity compared to eutomer
3. qualitative differences
   - enantiomers may act at different receptor sites
4. behaviour of racemate is different from either enantiomer

Question 20

what are the pharmacokinetic differences in interaction between drug molecule and target molecule in absorption

Answer 20

1. most synthetic drugs cross biological membranes by passive diffusion
2. some are actively transported

Question 21

what are the pharmacokinetic differences in interaction between drug molecule and target molecule in distribution

Answer 21

1. protein binding
   - S enantiomer of disopyramide shows lower plasma and renal clearance, longer half life and smaller volume of distribution than R isomer

Question 22

what are the pharmacokinetic differences in interaction between drug molecule and target molecule in metabolism

Answer 22

• in propanolol, S isomer is the eutomer
• R isomer is more rapidly metabolised than S isomer in propanolol

Question 23

what are the pharmacokinetic differences in interaction between drug molecule and target molecule in excretion

Answer 23

1. for many drugs, this is a passive process
2. might expect to see stereoselectivity for drugs that are actively secreted or reabsorbed

Question 24

give examples of drug interactions with the S or R isomers

Answer 24

• cimetidine interacts selectively with the R enantiomer of warfarin
• phenylbutazone interacts selectively with S isomer of warfarin

Question 25

describe the economics of enantiomers

Answer 25

generally cheaper to synthesise the racemate rather than a single enantiomer

Question 26

what is cis-trans isomerism

Answer 26

points of rigidity within a molecule can result in more than 1 form of the molecule
- a double bond has restricted rotation
- can have cis and trans isomers

Question 27

describe the different uses of tamoxifen and clomiphene

Answer 27

• Z tamoxifen is used in the treatment of oestrogen, dependent on breast cancer
• Z clomiphene is used in treatment of ovulatory failure

Question 28

what is conformation

Answer 28

where spatial arrangement of atoms can be interconverted without breaking/remaking bonds
- rotation about single bonds
- small but measurable energy differences between conformers

Question 29

give an example of conformation

Answer 29

thyroxine and triiodothyronine

Question 30

what are the implications of conformation for drug design

Answer 30

1. spatial arrangement of key functional groups is important
2. seemingly minor changes to the structure can have consequences on the conformation of the molecule and the biological properties of the drug